Neuronal cell death and axonal degeneration are major pathological features of most neurodegenerative diseases16. Because neuronal cell loss is most commonly associated with symptom onset, considerable research efforts have been focused on understanding the mechanisms that regulate neuronal cell death in order to prevent neuronal loss in these diseases. However, it is now appreciated that axon degeneration can often precede both neuronal cell death and symptom onset, suggesting that it may be an underlying etiology of neurodegenerative diseases thus prompting researchers to pursue it as a novel therapeutic point of intervention 16. One commonly observed form of axon degeneration, termed Wallerian degeneration, is best known as the program responsible for destroying and clearing axon segments distal to a physical injury site. However, the Wallerian degeneration program operates not only in injury induced axon degeneration but also during the pathological axon degeneration associated with several neurodegenerative diseases1,2. Our collaborators and we have recently identified the first endogenous gene, SARM1, responsible for executing the Wallerian degeneration program in both invertebrates and vertebrates7. Here, we propose to further our understanding of axon degeneration in the mammalian nervous system by using SARM1 as a novel entry point for revealing new molecular mechanisms of Wallerian degeneration of axons. We will first focus on examining SARM1 localization and function in injured neurons and their axons, and determine how SARM1 promotes Wallerian degeneration of axons following injury. We next aim to identify and characterize novel components of the Wallerian degeneration pathway by isolating SARM1 interacting proteins and using a candidate approach to screen through genes that may be part of an evolutionary conserved SARM1 signaling pathway. Finally, we will assess the role of the SARM1 signaling pathway in vivo in injury-induced and chemically-induced neuropathies. We expect that the experiments outlined in this proposal will lead to a better understanding of mechanisms that regulate axon degeneration and will likely be helpful in identifying novel targets for treating a number of neurodegenerative diseases.